title: The novel somatostatin receptor 2/dopamine type 2 receptor chimeric compound BIM-23A758 decreases the viability of human GOT1 midgut carcinoid cells.
abstract: The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system coexpress somatostatin receptors (SSTRs) and dopamine type 2 receptors (D2R), thus providing a rationale for the use of novel SSTR2/D2R chimeric compounds in NET disease. Here we investigate the antitumor potential of the SSTR2/D2R chimeric compounds BIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonist BIM-23023 and the selective D2R agonist BIM-53097 on human NET cell lines of heterogeneous origin. While having only minor effects on human pancreatic and bronchus carcinoid cells (BON1 and NCI-H727), BIM-23A758 induced significant antitumor effects in human midgut carcinoid cells (GOT1). These effects involved apoptosis induction as well as inhibition of mitogen-activated protein kinase and Akt signaling. Consistent with their antitumor response to BIM-23A758, GOT1 cells showed relatively high expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cells highly express the short transcript variant of D2R. In contrast to BIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as the individual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097 induced no or only minor antitumor responses in the examined NET cell lines. Taken together, our findings suggest that the novel SSTR2/D2R chimeric compound BIM-23A758 might be a promising substance for the treatment of NETs highly expressing SSTR2 and D2R. In particular, a sufficient expression of the short transcript variant of DR2 might play a pivotal role for effective treatment.
authors.affiliation: Department of Internal Medicine II, University Hospital Campus Grosshadern, Ludwig Maximilians University, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zitzmann
authors.forename: Sandra
authors.initials: S
authors.lastname: Andersen
authors.forename: George
authors.initials: G
authors.lastname: Vlotides
authors.forename: Gerald
authors.initials: G
authors.lastname: Spöttl
authors.forename: Shengwen
authors.initials: S
authors.lastname: Zhang
authors.forename: Rakesh
authors.initials: R
authors.lastname: Datta
authors.forename: Michael
authors.initials: M
authors.lastname: Culler
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002276:Carcinoid Tumor / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics; D017481:Receptors, Somatostatin / Q000819:agonists / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D011993:Recombinant Fusion Proteins; C103631:somatostatin receptor 3; C101130:somatostatin receptor type 1; D013004:Somatostatin; C093733:somatostatin receptor 2; C531242:TBR-760; D004298:Dopamine